Lung cancer is the leading cause of cancer death in the U.S. One of the major obstacles in treating lung cancer is its late presentation, when the options for treatment are primarily palliative. The lack of effective therapy underscores the urgency to reevaluate our current management strategy and explore new frontiers of treatment such as chemoprevention in high-risk individuals. Previous studies have shown that former heavy smokers (equal to or > 30 pack years), particularly those with airflow obstruction and/or a history of stage I non-small cell lung cancer (NSCLC) who have had curative resection, continue to have significantly elevated cancer risk than never smokers. Therefore, the overall objective of this pilot proposal is to evaluate the feasibility and effectiveness of Celecoxib, a cyclooxygenase-2 (Cox-2) inhibitor, for lung cancer prevention in this high-risk population. To achieve this objective, 180 former heavy smokers, with either evidence of airflow obstruction and/or prior stage I NSCLC, will be recruited into a double blind, placebo controlled, crossover pilot study. Subjects will be treated in random order with either 6 months of oral Celecoxib as a chemopreventive agent first, followed by 6 months of placebo or vise versa. All subjects will be followed with serial tests including sputum analysis, LIFE bronchoscopy and spiral CT according to a pre- determined algorithm. Celecoxib will be evaluated for its impact on cellular and molecular events associated with lung carcinogenesis: including 1) modulation of a panel of biomarkers of field cancerization (Ki-67, phenotypic modulations of bronchial histopathology, alteration of prostaglandin E2 production in bronchoalveolar lavage fluid, expression of Cox-2, EGFR, p27,p16, bcl-2, apoptosis index, cyclin D1 and E, GSTP1 methylation, GSTP1, GSTM1 and CYP1A1 polymorphisms, P53 polymorphisms and p16 methylation; 2) regulation of arachidonic acid metabolism; 3) antitumor immunity; and 4) angiogenesis in the lung microenvironment. The safety and side effect of long term use of Cox-2 inhibition will be monitored with the modified NCI common toxicity criteria scale and serial adverse reaction questionnaire. Moreover, serial bronchial tissue, sputum, buccal smear, blood (plasma and buffy coat), and urine specimens, respiratory and health questionnaires will be archived for future analysis. The finding from this pilot project will provide important insight into the design and conduct of future chemopreventive trials.